Epidermal growth factor receptor (EGFR or HER-1) is central to human tumorigenesis, and dysregulation of this receptor is mainly due to increased expression [Arteaga, C. L. 2002. Semin. Oncol. 29(Suppl 14):3-9] and mutations in different domains of the receptor [Boerner, J. L., A. Danielsen, and N. J. Maihle. 2003. Exp. Cell Res. 284: 111-121]. HER-1 is overexpressed in most epithelial cancers including breast/triple-negative breast cancer (TNBC; 14-90%) [Gluz, O., et. al. 2009. Ann. Oncol. 20: 1913-1927, Pintens, S., et al. 2009. J. Clin. Pathol. 62: 624-628], non-small cell lung (40-80%) [Hirsch, F. R., et al. 2003. J. Clin. Oncol. 21: 3798-3807], head and neck (80-100%), colorectal (25-77%), and other cancers. HER-1 overexpression in tumors is responsible for aggressiveness, poor prognosis, decreased survival, poor response to therapy, and development of resistance [Arteaga, C. L., and J. Baselga. 2004. Cancer Cell 5: 525-531]. HER-1 forms heterodimers with other human epidermal growth factor receptor (HER) family members like HER-2, HER-3, and HER-4 resulting in aggressive forms of cancer with lower survival rates [Brabender, et al. 2001. Clin. Cancer Res. 7: 1850-1855].
The development of antibodies targeting HER-1 is mainly dependent on structural studies that help outline the details of the receptors and other conformational changes affecting its activation and downstream signaling. HER-1 signaling is highly dependent on ligand binding, which is a key factor in releasing the dimerization arm of the receptors [Ferguson, K. M., et al. 2003. Mol. Cell 11: 507-51], and this explains why many of the anti-HER-1 antibodies are directed toward the ligand-binding region. Cetuximab, a humanized mAb, binds HER-1, prevents ligand binding, and is Food and Drug Administration-approved for the treatment of metastatic colorectal cancers with high HER-1 expression [Li, S., et al. 2005. Cancer Cell 7: 301-311]. However, the emergence of resistance to cetuximab has led to the proposal that other mechanisms exist that are independent of ligand binding, and this has led to the development of other antibodies with key epitopes that are different from cetuximab. For instance, activation of other HER family receptors may help in the stabilization of HER-1 even in the absence of ligand binding [Sawano, A., et al. 2002. Dev. Cell 3: 245-257].
Further, mAbs have additional limitations such as repeated frequency of i.v. treatments and infusion reactions that can be lethal in some patients [Grothey, A. 2006. Oncology (Huntingt.) 20(Suppl 10): 21-28] Inhibition of metastasis by these agents has been shown to be nonspecific in both preclinical and clinical settings, and the toxicity caused by these agents clearly illustrates the potential risks of their continuous use in the clinic. Given these caveats, there is an urgent unmet need for developing more efficacious, safer, and less toxic anti-HER-1 agents.
Like HER-1, HER-3 (ErbB3) is a member of the human epidermal growth factor family of receptors. Efforts at targeting HER-3 have lagged behind the other members of this family, due in part to its impaired kinase activity. However, several recent studies have shown that HER-3 may be an attractive target against many types of cancer. HER-3 is frequently up-modulated in cancers with HER-1 or HER-2 overexpression, and HER-3 may provide a route for resistance to agents that target EGFR or HER-2. Currently, therapeutic monoclonal antibodies such as AMG 888 and MM-121 specifically target HER-3 and are currently being evaluated in clinical trials. Yet again, great limitations exist with TKIs and monoclonal antibodies, including: severe toxicities, repeated treatments, high costs, development of resistance, and limited duration of action.
Apart from the HER family receptors, the insulin-like growth factor (IGF-1R) has also emerged as a key regulator of tumorigenesis in colorectal cancer [Lu Y., et al. International Journal of Cancer 2004, 108(3):334-341, Haluska P, et al. 2008. Molecular Cancer Therapeutics 7(9):2589-2598]. Accordingly, there is a need for new agents that target HER-1, HER-3 and IGF-1R for the treatment of cancer.